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Tofacitinib regulates synovial inflammation in psoriatic arthritis, inhibiting STAT activation and induction of negative feedback inhibition

W Gao, T McGarry, C Orr, J McCormick, D J Veale, U Fearon. - Annals of the Rheumatic Diseases. 2015 Sep 9. doi:10.1136/annrheumdis-2014-207201

Psoriatic arthritis (PsA) is a chronic inflammatory arthritis associated with psoriasis (Ps) and characterised by synovitis and progressive destruction of articular cartilage and bone. Recently developed agents for PsA target IL12p40, IL-6 and IL-17, several of which signal through the JAK family of receptor-associated tyrosine kinases. Tofacitinib is a drug of the JAK inhibitor class and is currently approved for the treatment of RA in 27 countries. This study evaluated the effect of tofacitinib on proinflammatory mechanisms in PsA by culturing PsA synovial fibroblasts (PsAFLS) and ex vivo PsA synovial explants with 1 mM tofacitinib for 72 hours.

This study showed that tofacitinib inhibits proinflammatory and invasive mechanisms which are critically involved in the pathogenesis of PsA. It significantly decreases pSTAT1, pSTAT3 in PsAFLS and PsA synovial explant cultures ex vivo and increases SOCS3 and PIAS3 expression demonstrating negative feedback inhibition. Tofacitinib significantly decreases PsAFLS invasion, migration and network formation and the spontaneous secretion of key proinflammatory cytokines, the MMP/TIMP ratio and NFκBp65 expression. These data support a role for blockade of JAK-STAT signalling pathways in the treatment strategy for PsA.

Keywords: JAK, Tofacitinib, Preclinical, MOA

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Upload date: October 2015

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